27 Jul Hebrew University Study Finds New Brain Circuit Involved in Addiction and May Be Target for Treating Dependence

MedicalResearch.com Interview with:

Prof. Kupchik

Prof. Yonatan M. Kupchik PhD and

L. Levi

Liran Levi, PhD student
Faculty of Medicine at Hebrew University

MedicalResearch.com: What is the background for this study?

Response: Motivated behavior is driven by a group of brain regions called collectively the reward system. This neural system is at the heart of every decision we make about our actions – it integrates information about the world and decides whether to perform a behavior or not based on the predicted reward/benefit. The key molecule in this process is dopamine – whenever we perform a behavior that provides a reward dopamine is released in the reward system and reinforces this behavior. Drugs of abuse exploit this system – they cause abnormally high levels of dopamine, and thus force the reward system to seek drugs constantly, even after prolonged withdrawal. From a neurobiological perspective, that is how we view substance dependence – the reward system drives people to seek for the reward.

MedicalResearch.com: What are the main findings?

Response:  The reward system, and particularly a region called the Ventral Pallidum, contains also a small network of neurons whose activation suppresses dopamine release and drives aversion and negative emotions. Our study aimed at understanding whether these “aversive” neurons of the reward system also play a role in the process of substance dependence, withdrawal and relapse. We recorded in mice the activity of these neurons during the process of cocaine consumption, prolonged withdrawal, and re-exposure to cocaine after withdrawal. We discovered that these “aversion” neurons are highly sensitive to the state of the mouse – they are silent when the animal is consuming the drug, but reach their peak activity after prolonged withdrawal, possibly underlying the negative emotional state that emerges during withdrawal. Most interestingly, a single shot of cocaine after withdrawal, that reinstates the hedonic feelings induced by cocaine, also re-silences these neurons, suggesting that they may act as a switch between “abstinence” and “consumption” states.

Lastly, we wanted to see what happens when we inhibit these aversion neurons artificially when the mice are re-exposed to cocaine after withdrawal. A bit to our surprise, we saw that inhibiting these aversion neurons enhanced cocaine seeking behavior. Thus, while during abstinence these aversion neurons are highly active and may drive the negative emotions linked to withdrawal, during re-exposure to the drug they might act as a defense mechanism, contradicting the increase in dopamine levels.

Unfortunately there are no medications today that can target these neurons directly and selectively. Even though the technology for targeting specific neurons in the human brain still needs to be developed, our findings may highlight, in the future, these aversion neurons of the reward system as potential targets for treating substance dependence.

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: This study presents a new circuit in the reward system of the brain that is involved in addiction. It would be important to see that it also affects seeking for other drugs, such as opiates. It would also be interesting to manipulate these aversion circuits in other ways (for example, enhance their activity) to see if they can serve as a protective mechanism against drug seeking

Disclosures

Nothing to disclose. The study is part of the activity of the Center on Drug Addiction Research (ICARe) at the Institute for Medical Research Israel-Canada of the Hebrew University.

Citation:
Liran A. Levi et a A ventral pallidal glutamatergic aversive network encodes abstinence from and reexposure to cocaine.Sci. Adv.11,eadu6074(2025).DOI:10.1126/sciadv.adu6074

https://www.science.org/doi/full/10.1126/sciadv.adu6074

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Last Updated on July 27, 2025 by Marie Benz MD FAAD